CD4 T cell responses are essential for host survival of Mycobacterium tuberculosis (Mtb) infection, but the properties of host protective CD4 T cells remain poorly understood. Accordingly, there are no correlates of protection against Mtb infection, which is a major barrier to developing new vaccine and therapeutic strategies. Previously, we previously found that the pulmonary effector T cell response against Mtb is composed of two major subpopulations that preferentially localize to either the lung parenchyma or lung blood vasculature. Intravascular Mtb-specific CD4 T cells display greater potential for cytokine production as well as active production of interferon-gamma (IFNg) in vivo compared to their tissue parenchymal counterparts. However, CD4 T cells with the ability to migrate into the tissue parenchyma were highly protective against Mtb infection, while CD4 T cells that were high producers of IFNg but poorly migrate into the lung displayed minimal control of the infection. Much of the work in the TBU in the past year has been to further explore these central observations on T cell immunity to Mtb infection. We have examined the role of the classic Th1 inducing factors IL-12 and T-bet in the regulation of the production of the protective parenchymal and non-protective intravascular effector CD4 T cell subsets. While IL-12 and T-bet are required for IFNg production and host-survival, we find that they also have unexpected negative effects on the differentiation state and protective capacity of Mtb-specific CD4 T cells by favoring the development of a large population of terminal effector-like CX3CR1+ Th1 cells that cannot migrate into the lungs and do not contribute to control of pulmonary infection. Collectively our data show that the T cell polarizing activities of the IL-12 and T-bet must be restrained in order to optimally produce populations of effector T cells with optimal lung-homing and host-protective ability during Mtb infection. IFNg is required for host protection against Mtb infection, and due to the severity of disease in its absence, the prevailing view is that IFNg is the primary mechanism of CD4 T cell dependent immunity to Mtb infection. There is anecdotal evidence that CD4 T cells can contribute to Mtb control in an IFNg-independent manner, but it is not clear how important these molecules are in relation to IFNg or what effector molecules besides IFNg can suppress growth of Mtb in vivo. We have quantified the contribution of CD4 T cell-derived IFNg to control of Mtb infection in different infection sites. We found that the major role of IFNg is in control of Mtb infection at extrapulmonary sites, and that the role of CD4 T cell-derived IFNg in the lung is minimal. Moreover, the inhibitory receptor PD-1 is required to prevent the lethal over-production of IFNg by CD4 T cells. Therefore, our data indicate that defects in IFNg production cannot explain the inability to control Mtb infection, and the major mechanisms of CD4 T cell-dependent control of Mtb infection remain unknown. Our group has also sought to test our hypotheses based on the murine model in the more relevant model species rhesus macaques. We have found that primary effector CD4 T cells in rhesus macaques do not differentiate into terminal effector like cells. Using the intravascular staining approach in non-human primates, we find that all Mtb-specific effector CD4 T cells present in granulomas have migrated into the tissue parenchyma. Therefore, unlike mice, rhesus macaque CD4 T cells do not develop the defects in lung homing associated with terminal differentiation. We also examined the distribution of CD4 T cells inside of granulomas. We found that 80-90% of the CD4 T cells are distributed in the peripheral lymphocyte cuff of the granuloma, and only a small fraction of CD4 T cells are present in the macrophage rich core where the bacteria are replicating. Therefore, defects in intralesional positioning limit interactions of CD4 T cells with infected macrophages, and may pose a major barrier to control of Mtb infection. These data also highlight the importance of further testing hypotheses based on murine studies in non-human primate Mtb infection.